1,4-disubstituted piperazines useful in the therapy of the asthma and of the inflammation of the respiratory tract

ABSTRACT

Compounds of formula (I): ##STR1## wherein Ra, Rb, B and D have the meanings reported in the disclosure, processes for making the same, and methods of using the same in the treatment of asthma and/or inflammation of the respiratory tract are disclosed.

This is a national stage entry application of International PCTApplication Serial PCT/EP93/02264, filed on Aug. 24, 1993 and publishedas WO94/07856 on Apr. 14, 1994.

The present invention relates to heterocyclic amines, a process for thepreparation thereof and pharmaceutical compositions containing them.

More particularly, the invention relates to compounds of formula (I).##STR2## the single enantiomeric and diastereomeric forms thereof, themixtures thereof and the salts thereof with pharmaceutically acceptableacids and bases, wherein:

B is a --CO--, --CH₂ OCO--, --CH₂ OCS--, --CH₂ NHCO--, --CH₂ NHCS--group;

D is a 5-6 membered heterocycle with 1-3 nitrogen atoms optionallysubstituted with 1 or 2 amino, mono-C₁ -C₆ -alkylamino, mono-C₃ -C₇-alkenyl- or mono-C₃ -C₇ alkynylamino, di -C₁ -C₆ -alkylamino, (C₁-C₆)alkyl (C₃ C₇)alkenylamino, piperidin-1-yl, morpholin-4-yl,pyrrolidin-1-yl groups;

Ra and Rb are hydrogen, C₁ -C₃ alkyl or, taken together with the carbonatom they are linked to, they form a C₃ -C₆ -cycloalkyl group;

n is an integer from 1 to 4.

Examples of C₁ -C₃ or C₁ -C₆ -alkyl groups are methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl.

Examples of 5- or 6-membered heterocyclic groups with 1-3 nitrogenatoms, optionally substituted with 1-2amino groups, are:[2,6-bis(diethylamino)-4-pyrimidinyl],[2,6-bis(allylamino)-4-pyrimidinyl], [2,6-bis(amino)-4-pyrimidinyl],[2,6-bis(pyrrolidin-1-yl)-4-pyrimidinyl],[4,6-bis(allylamino)-1,3,5-triazin-2-yl],[4,6-bis(diethylamino)-1,3,5-triazin-2-yl],[4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl],[3,6-bis(diethylamino)pyridin-2-yl],[3,6-bis(pyrrolidin-1-yl)pyridin-2-yl],[3,6-bis(allylamino)pyridin-2-yl],[3,6-bis(propargylamino)pyridin-2-yl],[3,6-bis(N-ethyl-N-allylamino)pyridin-2-yl], [3-ethylaminopyridin-2-yl].

Examples of mono-C₁ -C₆ -alkylamino groups are methylamino, ethylamino,propylamino, isopropylamino, n-butylamino, t-butylamino.

Examples of mono-C₃ -C₆ -alkenyl- or mono-alkynylamino groups areallylamino, propargylamino.

Examples of di -C₁ -C₆ -alkylamino groups are dimethylamino,diethylamino, methylethylamino, methylpropylamino, methylisopropylamino,diisopropylamino, methyl n-butylamino.

Examples of (C₁ -C₆)alkyl-(C₃ -C₇)alkenylamino groups aremethylallylamino, ethylallylamino, propylallylamino,isopropylallylamino.

Ra and Rb are preferably hydrogen, methyl, ethyl or, if taken togetherwith the carbon atom they are linked to, are a cyclopropyl, cyclopentylor cyclohexyl group.

Particularly preferred compounds (I) are those in which B is a --CO-- or--CH₂ OCO-- group; D is an heterocycle selected from the groupconsisting of [2,6-bis(pyrrolidin-1-yl)-4-pyrimidinyl],[4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl],[3,6-bis(diethylamino)-pyridin-2-yl ]and [3-ethylaminopyridin-2-yl ];Ra, which is the same as Rb, is hydrogen or methyl and n is 1.

The acid and basic groups can be salified respectively withpharmaceutically acceptable bases and acids. The non toxic salts thusobtained fall within the scope of the invention, as well as the singleenantiomers, diastereomers, diastereomeric mixtures and racemates of thecompounds of formula (I). Compounds (I) can be salified with bothinorganic and organic acids which are pharmaceutically acceptable, suchas hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric,nitric or sulfuric, acetic, ossalic, tartaric, citric, benzoic,glycolic, gluconic, glucuronic, succinic, maleic, fumaric acids, etc.The carboxy group can be salified with bases of various nature, with theonly proviso that the salts are pharmaceutically acceptable. Examples ofsaid salts comprise those with: ammonium, sodium, potassium, calcium,magnesium, aluminium, iron, zinc, copper, or salts with pharmaceuticallyacceptable organic bases such as arginine, lysine, histidine,methylamine, ethylamine, dimethylamine, dibenzylamine, morpholine,phenylglycin and D-glucosamine.

Prolinamides with piperazinquinazoline are described to beACE-inhibitors (Sankyo Co., JP 82 91,987; C.A., 97:198218w, 1982).N-Carbamoylprolinamides with N-methylpiperazine are known to befilaricidal (Indian J. Chem., Sect. B, 1987, 26B(8), 748-751).

The compounds of the invention showed useful pharmacological properties,particularly as far as the treatment of bronchial hyper-reactivity isconcerned.

Bronchial hyper-reactivity is a clinical symptom of asthma and it isbelieved to be a direct consequence of an abnormal and latentcontractility and sensitivity of the bronchial mucosa.

Bronchial hyper-reactivity can cause acute crisis of asthma afterphysical practice, and/or after exposure to external stimuli such as theinhalation of fog, pollutants, allergens and autacoids.

The bronchial hyper-reactivity conditions may be simulated by anexperimental model consisting in the PAF infusion (600 μg/1) in maleguinea-pigs weighing 400-450 g, kept under forced ventilation underurethane and pancuronium bromide anaesthesia.

PAF, which is one of the most important mediators involved in theinflammatory process of the airways, after infusion for 1 hour, causesan hyperreactivity reaction (bronchocostriction) to specific anddifferent substances.

The activity of the compounds of the invention, in the consideredpharmacological model, is shown by the prevention of the PAF-inducedhyper-reactivity, measured as increase of the pulmonary insufflatorypressure (measured according to the modified procedure of Konzett andRossler, Naun. Schmied. Arch. Exper. Pathol. Pharmacol. 191, 71, 1970).

The compounds of the invention, which are administered 10 minutes beforethe PAF administration in dosages which vary between 2 and 50 μg/kg,demonstrate a protective action which lasts at least 4-6 hours andresults in a reduction of the PAF-induced hyperreactivity. Suchpharmacological effects are dose related.

From what has been shown above it is clear that the compounds of theinvention can be used in human therapy in the treatment of asthmatic andobstructive conditions of the respiratory tract, in the treatment ofinflammatory phlogosis. For the intended therapeutic uses, the compoundsof the invention will be administered in the form of pharmaceuticalcompositions which can be prepared with conventional excipients andtechniques such as, for example, those described in Remington'sPharmaceutical Sciences Handbook, Mack Pub. Co., N.Y., USA, 17th ed.,1985 adapted for administration by intramuscular, intravenous, oral,aerosol and rectal routes.

The daily dose will depend on several factors such as the gravity of thepathology and the condition of the patient: it will normally consist of1 to 50 mg of a compound of formula (I) for a patient weighing 70 one ormore times a day.

The compounds of formula (I) are prepared by reacting a compound offormula (II) ##STR3## wherein B and D are as above defined, with acompound of formula (III) ##STR4## wherein Ra, Rb and n have the abovedescribed meanings; R is a C₁ -C₆ -alkyl, benzyl, allyl group or anyother group which can easily be removed; E is halogen (chlorine,bromine), N-imidazolyl, OH, O-hydroxysuccinimidyl or, taken togetherwith the carbonyl group, it forms a mixed anhydride with a carboxylic orsulfonic acid (for example, trifluoromethanesulfonic acid), to givecompounds of formula (Ia) ##STR5##

Compounds of formula (Ia) can be transformed into the compounds offormula (I) by means of conventional reactions such as:

a) when R is C₁ -C₆ -alkyl, hydrolysis with mineral bases such assodium, potassium, lithium hydroxides at various concentrations and invarious solvents (such as methanol, ethanol, dimethylformamide);

b) when R is allyl or benzyl, catalytic hydrogenation with variouscatalysts (such as palladium on charcoal in various concentrations,nikel-Raney, palladium tetrakis(triphenylphosphine), and the like) andin various solvents (such as methanol, ethanol, toluene, methylenechloride) or by means of hydrogen transfer procedures, such as thosewith ammonium formate, cyclohexene or sodium hypophosphite in thepresence of palladium on charcoal in solvents such as water, loweralcohols or mixtures thereof.

The reaction of compound (II) with compound (III) is usually carried outin an inert solvent and in the presence of a suitable base. In caseE--CO-- is a carboxy group (E═OH), the reaction is carried out in aninert solvent and in the presence of condensing agents such ascarbodiimides, isonitriles, and the like.

The preparation of the compounds of formula (II) is carried out startingfrom an acid of formula (IV) ##STR6## wherein R' is a suitableprotecting group which can be removed compatibly with the reactionsdescribed below and with the functional groups present in the molecule.Convenient protecting groups of formula R' can be: tert-butoxycarbonyl,methoxycarbonyl, 9-fluorenoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,allyloxycarbonyl, benzyloxycarbonyl. Compounds of formula (IV) arecommercially available or they can be prepared from proline by means ofconventional and widely known reactions, which are reported inliterature. If said compounds are not commercially available as theenantiomerically pure forms thereof, they can be resolved withconventional methods such as salification with optically active basesand separation of the diastereomeric salts.

The transformation of the products of formula (IV) in those of formula(V) ##STR7## wherein R' has the above defined meanings, can be effectedwith conventional reactions.

Particularly:

a) the synthesis of compounds of formula (Va): ##STR8## starting fromcompounds of formula (IV), can be carried out by transformation of thecarboxy group into a succinimido ester, acid chloride, mixed anhydride,imidazolide or other reactive derivatives of the carboxy group andcondensation thereof with an amine of ##STR9## b) the synthesis ofcompounds of formula (Vb): ##STR10## in which X═O or S, starting fromcompounds of formula (IV), can be performed by reduction of the carboxygroup or of a corresponding mixed anhydride or a carboxy esterderivative thereof to primary alcohol (CH₂ OH), which can be convertedinto a carbamate or thiocarbamate by reaction with carbonyldiimidazoleor thiocarbonyldiimidazole and subsequently with an amine of formula(VI). The reduction of the carboxy group of proline or of a mixedanhydride thereof to alcohol can conveniently be carried out withreducing agents such as diborane or a borohydride of an alkali oralkaline-earth metal;

c) the synthesis of compounds of formula (Vc): ##STR11## in which X═O orS, can be carried out by conversion of the alcohols, obtained asdescribed in point b), into the corresponding amines according to theMitsunobu's reaction using ditertbutylimino dicarboxylate as anucleophilic agent and subsequent deprotection of the amino group withgas hydrochloric acid or with trifluoroacetic acid. The resulting aminescan be converted into the corresponding ureas or thioureas by reactionwith carbonyl- or thiocarbonyldiimidazole respectively and,subsequently, with an amine of formula (VI).

The transformation of compounds of formula (V) into compounds of formula(II) can be performed by conventional removing methods which arespecific and selective for the used protecting group and particularly,in the case of BOC-derivatives, with trifluoroacetic acid ortrimethylsilyl iodide.

Compounds of formula (III) are obtained according to conventionalprocesses reported in literature.

The following examples and preparations further illustrate theinvention. The concentrations are expressed as % in w/v. The describedcompounds should be considered as racemic mixtures, if not otherwisestated by means of the symbols (+) and (-). The malonic acid monoalkyl-or monobenzyl esters and the acyl chlorides thereof are known inliterature or anyhow they can be prepared according to conventionalmethods which are widely reported in literature.

EXAMPLE 1

A solution containing 2.5 g of BOC-L-proline in anhydrous THF (10 ml) isadded, at a temperature of 0° C., under inert gas atmosphere and withstirring, with 2.9 g of N-hydroxysuccinimide dissolved in 10 ml of THF.Said solution is added dropwise with a solution of 2.1 ml ofmorpholinoethylisonitrile in 5 ml of THF and stirring is continued atroom temperature for 2 hours; the reaction mixture is acidified with 1Nhydrochloric acid to acid pH (litmus paper) and is extracted with ethylacetate (3×10 ml). The combined organic extracts are concentrated undervacuum to crystallize the BOC-L-proline succinimido ester, which isseparated by filtration, to obtain 2.6 g, m.p. 128°-130° C. 1 g of theBOC-L-proline succinimido ester is dissolved in acetonitrile (7 ml), atroom temperature and under inert gas atmosphere, then, under stirring,0.97 g of N-[4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl]piperazinedissolved in acetonitrile (5 ml) are added. After 5 hours the reactionmixture is concentrated under vacuum to small volume, then it is addedwith a sodium bicarbonate saturated solution to slightly basic pH. Themixture is extracted with ethyl acetate (3×10 ml), then the combinedextracts are concentrated to small volume under vacuum. By addition ofethyl ether, 1.5 g of(-)-N-[(pyrrolidin-1-tertbutoxycarbonyl-2-yl)carbonyl]-N'-[4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl]piperazineprecipitate, m.p. 148° C. after recrystallization from diisopropylether, [(α]_(D) =-20.25° (c=2.01 in EtOH).

EXAMPLE 2

By reacting a solution of the BOC-proline N-hydroxysuccinimido ester inacetonitrile with a suitable N-substituted piperazine, according to theprocedure described in example 1, the following N,N'-disubstitutedpiperazines are obtained :

N'-[(pyrrolidin-1-tertbutoxycarbonyl-2-yl)carbonyl]-N-[2,6-bis(diethylamino)pyrimidin-4-yl]piperazine,

N'-[(pyrrolidin-1-tertbutoxycarbonyl-2-yl)carbonyl]-N-[2,6-bis(allylamino)pyrimidin-4-yl]piperazine,

(-)-N'-[(pyrrolidin-1-tertbutoxycarbonyl-2-yl)carbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine,m.p. 168°-170° C., [α]_(D) =-20.7° (c=2 in EtOH),

(+)-N'-[(pyrrolidin-1-tertbutoxycarbonyl-2-yl)carbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine,[α]_(D) =+20.2° (c=2.03 in EtOH),

N'-[(pyrrolidin-1-tertbutoxycarbonyl-2-yl)carbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine,m.p. 125° C.,

N'-[(pyrrolidin-1-tertbutoxycarbonyl-2-yl)carbonyl]-N-[4,6-bis(allylamino)-1,3,5-triazin-2-yl]piperazine,

N'-[(pyrrolidin-1-tertbutoxycarbonyl-2-yl)carbonyl]-N-[4,6-bis(diethylamino)-1,3,5-triazin-2-yl]piperazine,

(-)-N'-[(pyrrolidin-1-tertbutoxycarbonyl-2-yl)carbonyl]-N-[3,6-bis(diethylamino)pyridin-2-yl]piperazine,[α]_(D) =-19.3° (c=2.07 in EtOH),

(+)-N'-[(pyrrolidin-1-tertbutoxycarbonyl-2-yl)carbonyl]-N-[3,6-bis(diethylamino)pyridin-2-yl]piperazine,[α]_(D) =+19.8° (c=2.01 in EtOH),

N'-[(pyrrolidin-1-tertbutoxycarbonyl-2-yl)carbonyl]-N-[3,6-bis(pyrrolidin-1-yl)pyridin-2-yl]piperazine,

N'-[(pyrrolidin-1-tertbutoxycarbonyl-2-yl)carbonyl]-N-[3,6-bis(allylamino)pyridin-2-yl]piperazine,

N'-[(pyrrolidin-1-tertbutoxycarbonyl-2-yl)carbonyl]-N-[3,6-bis(N-ethyl-N-allylamino)pyridin-2-yl]piperazine,

N'-[(pyrrolidin-1-tertbutoxycarbonyl-2-yl)carbonyl]-N-[3-ethylaminopyridin-2-yl]piperazine.

EXAMPLE 3

2.54 ml of trifluoroacetic acid are added, under stirring and inert gasatmosphere, to a solution of 1.4 g of(-)-N'-[(pyrrolidin-1-tertbutoxycarbonyl-2-yl)carbonyl]-N-[4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl]piperazinein 10 ml of methylene chloride.

After 3 hours at room temperature, the reaction mixture is added with INNaOH to basic pH, then it is extracted with methylene chloride andrepeatedly washed with water. The combined organic extracts are driedover sodium sulfate and the solvent is evaporated off under reducedpressure. The crude product is crystallized from ethyl ether, to give950 mg of(-)-N'-[(pyrrolidin-2-yl)carbonyl]-N-[4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl]piperazine,m.p. 143° C., [α]_(D) =-65.75° (c=0.23 in EtOH).

EXAMPLE 4

By reacting the N,N'-disubstituted piperazine described in example 2according to the procedure described in example 3, the followingN'-substituted N-[(pyrrolidin-2-yl)carbonyl]piperazines are obtained:

N'-[(pyrrolidin-2-yl)carbonyl]-N-[2,6-bis(diethylamino)pyrimidin-4-yl]piperazine,

N'-[(pyrrolidin-2-yl)carbonyl]-N-[2,6-bis(allylamino)-pyrimidin-4-yl]piperazine,

(-)-N'-[(pyrrolidin-2-yl)carbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine,m.p. 172°-174° C., [α]_(D) =-56.6° (c=1.88 in EtOH),

(+)-N'-[(pyrrolidin-2-yl)carbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine,m.p. 148°-151° C., [α]_(D) =+53.5° (c=2.02 in EtOH),

N'-[(pyrrolidin-2-yl)carbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine, m.p. 137° C.,

N'-[(pyrrolidin-2-yl)carbonyl]-N-[4,6-bis(allylamino)1,3,5-triazin-2-yl]piperazine,

N'-[(pyrrolidin-2-yl)carbonyl]-N-[4,6-bis(diethylamino)-1,3,5-triazin-2-yl]piperazine,

(-)-N'-[(pyrrolidin-2-yl)carbonyl]-N-[3,6-bis(diethylamino)pyridin-2-yl]piperazine,oil [α]_(D) =-43.3° (c=2.56 in EtOH),

(+)-N'-[(pyrrolidin-2-yl)carbonyl]-N-[3,6-bis(diethylamino)pyridin-2-yl]piperazine,[α]_(D) =+48.4° (c=2.01 in EtOH),

N'-[(pyrrolidin-2-yl)carbonyl]-N-[3,6-bis(pyrrolidin-1yl)pyridin-2-yl]piperazine,

N'-[(pyrrolidin-2-yl)carbonyl]-N-[3,6-bis(allylamino)pyridin-2-yl]piperazine,

N'-[(pyrrolidin-2-yl)carbonyl]-N-[3,6-bis(N-ethyl-N-allylamino)pyridin-2-yl]piperazine,

N'-[(pyrrolidin-2-yl)carbonyl]-N-[3 -ethylaminopyridin-2 -yl]piperazine.

EXAMPLE 5

0.8 g of(-)-N'-[(pyrrolidin-2-yl)carbonyl]-N-[4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl]piperazinedissolved in 20 ml of acetonitrile are added, at 0° C. and understirring, with 0.22 g of potassium bicarbonate and with a solution of0.28 ml of ethyl malonyl chloride in 5 ml of acetonitrile. After 4 hoursat room temperature and under stirring, the reaction mixture is addedwith water (50 ml) and extracted repeatedly with ethyl acetate (3×20ml). The combined organic extracts are dried over sodium sulfate andsolvent is evaporated off under reduced pressure. The residue (0.86 g)is purified by silica gel chromatography (eluent hexane/AcOEt 1:1) togive 0.6 g of(-)-N'-[(1-ethoxymalonylpyrrolidin-2-yl)carbonyl]-N-[4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl]piperazine,m.p. 115° C., [α]_(D) =-23.95° (c=0.2 in EtOH).

EXAMPLE 6

According to the procedure described in example 5, starting from theN,N'-disubstituted piperazines described in example 4 and from themalonic acids monoester acid chlorides, optionally 2,2 disubstituted,the following piperazines are prepared:

N'-[(1-ethoxymalonylpyrrolidin-2-yl)carbonyl]-N-[2,6-bis(diethylamino)pyrimidin-4-yl]piperazine,

N'-[(1-ethoxymalonylpyrrolidin-2-yl)carbonyl]-N-[2,6-bis(allylamino)pyrimidin-4-yl]piperazine,

(-)-N'-[(1-ethoxymalonylpyrrolidin-2-yl)carbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine,m.p. 170°-172° C., [α]_(D) =-26.5° (c=2.19 in EtOH),

(+)-N'-[(1-ethoxymalonylpyrrolidin-2-yl)carbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine,m.p. 133°-135° C., [α]_(D) =+26.5° (c=2.14 in EtOH),

N'-[(1-ethoxymalonylpyrrolidin-2-yl)carbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine,m.p. 127-129° C.,

N'-[(1-ethoxymalonylpyrrolidin-2-yl)carbonyl]-N-[4,6-bis(allylamino)-1,3,5-triazin-2-yl]piperazine,

N'-[(1-ethoxymalonylpyrrolidin-2-yl)carbonyl]-N-[4,6-bis(diethylamino)-1,3,5-triazin-2-yl]piperazine,

(-)-N'-[(1-ethoxymalonylpyrrolidin-2-yl)carbonyl]-N-[3,6-bis(diethylamino)pyridin-2-yl]piperazine,m.p. hydrochloride 80°-85° C., [α]_(D) =-20.6° (free base, c=2.09 inEtOH),

(+)-N'-[(1-ethoxymalonylpyrrolidin-2-yl)carbonyl]-N-[3,6-bis(diethylamino)pyridin-2-yl]piperazine, [α]_(D)=+20.1° (c=2.01 in EtOH),

N'-[(1-ethoxymalonylpyrrolidin-2-yl)carbonyl]-N-[3,6-bis(pyrrolidin-1-yl)pyridin-2-yl]piperazine,

N'-[(1-ethoxymalonylpyrrolidin-2-yl)carbonyl]-N-[3,6-bis(allylamino)pyridin-2-yl]piperazine,

N'-[(1-ethoxymalonylpyrrolidin-2-yl)carbonyl]-N-[3,6-bis(N-ethyl-N-allylamino)pyridin-2-yl]piperazine,

N'-[(1-ethoxymalonylpyrrolidin-2-yl)carbonyl]-N-[3ethylaminopyridin-2-yl]piperazine,

N'-[(1-benzyloxymalonylpyrrolidin-2-yl)carbonyl]-N-[2,6-bis(diethylamino)pyrimidin-4-yl]piperazine,

N'-[(1-benzyloxymalonylpyrrolidin-2-yl)carbonyl]-N-[2,6-bis(allylamino)pyrimidin-4-yl]piperazine,

(-)-N'-[(1-benzyloxymalonylpyrrolidin-2-yl)carbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine,m.p. 144°-145° C., [α]_(D) =-26.5° (c=0.23 in EtOH),

N'-[(1-benzyloxymalonylpyrrolidin-2-yl)carbonyl]-N-[4,6-bis(allylamino)-1,3,5-triazin-2-yl]piperazine,

N'-[(1-benzyloxymalonylpyrrolidin-2-yl)carbonyl]-N-[4,6-bis(diethylamino)-1,3,5-triazin-2-yl]piperazine,

N'-[(1-benzyloxymalonylpyrrolidin-2-yl)carbonyl]-N-[4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl]piperazine,

N'-[(1-benzyloxymalonylpyrrolidin-2-yl)carbonyl]-N-[3,6-bis(diethylamino)pyridin-2-yl]piperazine,

N'-[(1-benzyloxymalonylpyrrolidin-2-yl)carbonyl]-N-[3,6-bis(pyrrolidin-1-yl)pyridin-2-yl]piperazine,

N'-[(1-benzyloxymalonylpyrrolidin-2-yl)carbonyl]-N-[3,6-bis(allylamino)pyridin-2-yl]piperazine,

N'-[(1-benzyloxymalonylpyrrolidin-2-yl)carbonyl]-N-[3,6-bis(N-ethyl-N-allylamino)pyridin-2-yl]piperazine,

N'-[(1-benzyloxymalonylpyrrolidin-2-yl)carbonyl]-N-[3-ethylaminopyridin-2-yl]piperazine,

N'-[(1-((2',2'-dimethyl)benzyloxymalonyl)pyrrolidin-2-yl)carbonyl]-N-[2,6-bis(diethylamino)pyrimidin-4-yl]piperazine,

N'-[(1-((2',2'-dimethyl)benzyloxymalonyl)pyrrolidin-2-yl)carbonyl]-N-[2,6-bis(allylamino)pyrimidin-4-yl]piperazine,

(-)-N'-[(1-((2',2'-dimethyl)benzyloxymalonyl)pyrrolidin-2-yl)carbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin -4-yl]piperazine,m.p. 104°-106° C., [α]_(D) =-43.2° (c=0.24 in EtOH),

N'-[(1-((2',2'-dimethyl)benzyloxymalonyl)pyrrolidin-2-yl)carbonyl]-N-[4,6-bis(allylamino)-1,3,5-triazin-2-yl]piperazine,

N'-[(1-((2',2'-dimethyl)benzyloxymalonyl)pyrrolidin-2-yl)carbonyl]-N-[4,6-bis(diethylamino)-1,3,5-triazin-2-yl]piperazine,

N'-[(1-((2',2'-dimethyl)benzyloxymalonyl)pyrrolidin-2-yl)carbonyl]-N-[3,6-bis(diethylamino)pyridin-2-yl]piperazine,

N'-[(1((2',2'-dimethyl)benzyloxymalonyl)pyrrolidin-2-yl)carbonyl]-N-[3,6-bis(pyrrolidin-1-yl)pyridin-2-yl)]piperazine,

N'-[(1-((2',2'-dimethyl)benzyloxymalonyl)pyrrolidin-2-yl)carbonyl]-N-[3,6-bis(allylamino)pyridin-2-yl]piperazine,

N'-[(1-((2',2'-dimethyl)benzyloxymalonyl)pyrrolidin-2-yl)carbonyl]-N-[3,6-bis(N-ethyl-N-allylamino)pyridin-2-yl]piperazine,

N'-[(1-((2',2'-dimethyl)benzyloxymalonyl)pyrrolidin-2-yl)carbonyl]-N-[3-ethylaminopyridin-2-yl]piperazine.

EXAMPLE 7

A solution of 0.5 g of (-)-N'-[(1ethoxymalonylpyrrolidin-2-yl)carbonyl]-N-[4,6-bis(pyrrolidin-yl)-1,3,5-triazin -2-yl]piperazinein 5 ml of methanol is added, under stirring and inert gas atmosphere,with 80 μl of sodium hydroxide (35% aqueous solution). Stirring iscontinued for 20 more hours, then the reaction mixture is brought toneutrality by addition of sodium bicarbonate, filtered over celite andthe solvent is evaporated off under reduced pressure. The crude product(0.52 g) is purified by silica gel chromatography (eluent methylenechloride/methanol 9:1) to obtain 0.43 g of (-)-N'-[(1-malonyl)pyrrolidin -2-yl) carbonyl]-N-[4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl]piperazine, m.p. 208°-211° C., [α]_(D) =21.7°(c=0.3 in EtOH).

EXAMPLE 8

1.5 g of(-)-N'-[(1-benzyloxymalonylpyrrolidin-2-yl)carbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazineare dissolved in a mixture of 20 ml of methanol and 6 ml of toluene,then 1.5 g of 10% palladium on charcoal are carefully added, undernitrogen protection. The resulting reaction mixture is subjected tocatalytic hydrogenation under atmospheric pressure, using an apparatussuch as the one described in VOGEL's Textbook of Practical OrganicChemistry, fifth Edition, Longman Scientific & Technical (USA John Wiley& Sons, Inc.), 1989, pages 89-92. After 10 minutes the reaction isfiltered through a celite plug to remove the catalyst and the solvent isevaporated off under reduced pressure. By crystallization of the crudeproduct from ethyl ether (5 r), 1.1 g of(-)-N'-[(1-(1'-malonyl)pyrrolidin-2-yl) carbonyl]-N-[2,6-bis-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine are obtained, m.p. 205°-207° C., [α]_(D)=-19.25° (c=0.21 in EtOH).

EXAMPLE 9

Following the procedures described in example 7 or in example 8,starting from the suitable esters described in example 6, the followingcarboxylic acids are prepared:

N'-[(1-(1'-malonyl)pyrrolidin-2-yl)carbonyl]-N-[2,6-bis(diethylamino)pyrimidin-4-yl]piperazine, m.p. 193°-195° C.,

N'-[(1-(1'-malonyl)pyrrolidin-2-yl)carbonyl]-N-[2,6-bis(allylamino)pyrimidin-4-yl]piperazine,

N'-[(1-(1'-malonyl)pyrrolidin-2-yl)carbonyl]-N-[4,6-bis(allylamino)-1,3,5-triazin-2-yl]piperazine, m.p. 200°-201° C.,

N'-[(1-(1'-malonyl)pyrrolidin-2-yl) carbonyl]-N-[4,6-bis(diethylamino)-1,3,5-triazin-2-yl]piperazine,

N'-[(1-(1'-malonyl)pyrrolidin-2-yl)carbonyl]-N-[3,6-bis(diethylamino)pyridin-2-yl]piperazine, m.p. sodium salt, 188°-191° C.,

N'-[(1-(1'-malonyl)pyrrolidin-2-yl) carbonyl]-N-[3,6-bis(pyrrolidin-1-yl)pyridin-2-yl]piperazine,

N'-[(1-(1'-malonyl)pyrrolidin-2-yl)carbonyl]-N-[3,6-bis(allylamino)pyridin-2-yl]piperazine,m.p. potassium salt, 179°-180° C.,

N'-[(1-(1'-malonyl)pyrrolidin-2-yl)carbonyl]-N-[3,6-bis(N-ethyl-N-allylamino)pyridin-2-yl]piperazine,

N'-[(1-(1'-malonyl)pyrrolidin-2-yl)carbonyl]-N-[3ethylaminopyridin-2-yl]piperazine, m.p. sodium salt 171°-174° C.,

N'-[(1-(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)carbonyl]-N-[2,6-bis(diethylamino)pyrimidin-4yl]piperazine,m.p. 166°-168° C.,

N'-[(1-(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)carbonyl]-N-[2,6-bis(allylamino)pyrimidin-4-yl]piperazine,

(-)-N'-[(1(2',2'-dimethyl-1'-malonyl)pyrrolidin2-yl)carbonyl]-N-[2,6-bis(pyrrolidin-1-yl) pyrimidin-4-yl]piperazine,m.p. 160°-163° C., [α]_(D) =-28.4° (c=0.2 in EtOH),

N'-[(1-(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)carbonyl]-N-[4,6-bis(allylamino)-1,3,5-triazin-2-yl]piperazine,m.p. 170°-172° C.,

N'-[(1(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)carbonyl]-N-[4,6-bis(diethylamino)-1,3,5-triazin-2-yl]piperazine,

N'-[(1(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)carbonyl]-N-[4,6-bis(pyrrolidin-1yl)-1,3,5-triazin-2yl]piperazine,m.p. 180°-181° C.,

N'-[(1(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)carbonyl]-N-[3,6-bis(diethylamino)pyridin-2-yl]piperazine,m.p. sodium salt 189°-192° C.,

N'-[(1-(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)carbonyl]-N-[3,6-bis(pyrrolidin-1-yl)pyridin-2-yl]piperazine,

N'-[(1-(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)carbonyl]-N-[3,6-bis(allylamino)pyridin-2-yl]piperazine,

N'-[(1-(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)carbonyl]-N-[3,6-bis(N-ethyl-N-allylamino)pyridin-2-yl]piperazine,m.p. potassium salt 195°-200° C.,

N'-[(1-(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)carbonyl]-N-[3-ethylaminopyridin-2-yl]piperazine,m.p. potassium salt 206°-208° C.

EXAMPLE 10

A solution of BOC-(L)-proline in 60 ml of anhydrous THF, cooled at -10°C. with brine, is added with 6.1 ml of triethylamine and 1 g of 4 Amolecular sieves, then, keeping the temperature below -5° C., a solutionof 4.16 ml of ethyl chloroformate in 5 ml of anhydrous THF is droppedtherein. After 30 minutes under stirring, the reaction mixture isfiltered to remove the triethylammonium chloride precipitate and thefiltrate is concentrated under reduced pressure to a volume of 30 ml.The resulting solution is dropped into a suspension of 7.5 g of sodiumborohydride in 50 ml of anhydrous THF, cooled at -10° C. with brine.After 2 hours the reaction mixture is added with 200 ml of an aqueoussaturated solution of sodium dihydrogen phosphate, keeping thetemperature at 0° C. with water/ice, then it is extracted with ethylacetate (3×50 ml). The combined organic extracts are washed repeatedlywith an aqueous saturated solution of sodium bicarbonate (3×30 ml),dried over sodium sulfate and the solvent is evaporated off underreduced pressure. The residue, by crystallization from hexane, yields6.1 g of BOC-(L)-prolinol, m.p. 59°-60° C., [α]_(D) =-54.9° (c=0.2 inEtOH).

EXAMPLE 11

A solution of 3 g of BOC-(L)-prolinol in 100 ml of anhydrous THF, cooledat 0° C. with water/ice, under stirring and inert gas atmosphere, isadded with 2.9 g of carbonyldiimidazole in portions, then the reactionmixture is warmed to room temperature and stirring is continued for 3hours. Said solution is added with 4.5 g ofN-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine in portions andstirring is continued for 18 hours. The reaction mixture is added with400 ml of an aqueous saturated solution of sodium dihydrogen phosphateand extracted with ethyl acetate (3×100 ml). The combined organicextracts are dried over sodium sulfate and the solvent is evaporated offunder reduced pressure. The residue (7.5 g) is purified by silica gelchromatography (eluent hexane/ethyl acetate 7:3), to obtain 5.5 g of(-)-N'-[(1-(tertbutoxycarbonyl) pyrrolidin-2-yl)methyloxycarbonyl]-N-[2,6-bis(pyrrolidin -1-yl)pyrimidin -4-yl]piperazine, m.p. 147° C., [(α]D-32'(c=0.25 in EtOH).

EXAMPLE 12

17.4 ml of trifluoroacetic acid are dropped into a solution of 10 g of(-)-N'-[(1-(tertbutoxycarbonyl) pyrrolidin-2-yl)methyloxycarbonyl]-N-[2,6bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine in 300 ml ofmethylene chloride. After about 18 hours, the reaction mixture is addedwith 400 ml of a 1N sodium hydroxide aqueous solution and extracted withmethylene chloride (3×150 ml). The combined organic extracts are washedwith water (2×100 ml), dried over sodium sulfate and the solvent isevaporated off under reduced pressure. By crystallization of the residuefrom diisopropyl ether/ethyl acetate 9:1, 6.5 g of(-)-N'-[(pyrrolidin-2-yl)methyloxycarbonyl]-N-[2,6-bis(pyrrolidin)-1-yl)pyrimidin-4-yl]piperazine are obtained, m.p. 137°-138° C., [α]_(D)=-8.7° (c=0.23 in EtOH).

EXAMPLE 13

A solution of 3.4 g of 2,2-dimethylmalonic acid mono-benzyl ester in 75ml of anhydrous dimethyl formamide, cooled at 0° C. with brine, understirring and inert gas atmosphere, is added with 3.77 g of1-hydroxybenzotriazole, 1.55 ml of N-methylmorpholine, 6 g of(-)-N'-[(pyrrolidin-2yl)methyloxycarbonyl]-N-[2,6 -bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine and finally 5.35 g ofN'-(3-dimethylaminopropyl-N-ethylcarbodiimide hydrochloride dissolved in25 ml of dimethylformamide, in this succession. The mixture is left towarm to room temperature, then stirring is continued for 18 more hours.The solvent is evaporated off under reduced pressure, then the reactionmixture is added with 200 ml of a sodium bicarbonate saturated aqueoussolution and extracted with ethyl acetate (3×100 ml). The combinedorganic extracts are dried over sodium sulfate and the solvent isevaporated off under reduced pressure. 10.2 g of a crude product areobtained, which is purified by silica gel chromatography (300 g ofsilica eluent petroleum ether/ethyl acetate 1:1), to obtain 6.5 g of(-)-N'-[(1-(3'-benzyloxy-2',2'-dimethylmalon-1'-yl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine,as a light brown foam. 6.45 g of(-)-N'-[(1-(3'-benzyloxy-2',2'-dimethylmalon-1'-yl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazineare dissolved in a mixture of 100 ml of methanol and 40 ml of toluene.Said solution is carefully added with 0.65 g of 10% palladium oncharcoal and the resulting reaction mixture is subjected to catalytichydrogenation under atmospheric pressure using an apparatus such as theone described in VOGEL's Textbook of Practical Organic Chemistry, fifthEdition, Longman Scientific & Technical (USA John Wiley & Sons, Inc.),1989, pages 89-92. After 10 minutes the reaction is filtered through acelite plug to remove the catalyst and the solvent is evaporated offunder reduced pressure. By crystallization of the crude product fromdiisopropyl ether, 5.5 g of(-)-N'-[(1-(2',2'-dimethylmalon-1'-yl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazineare obtained, m.p. 159°-160° C., [α]_(D) =-49.8° (c=0.21 in EtOH).

EXAMPLE 14

Following the procedures described in the examples 11, 12 and 13,starting from the suitable N-substituted piperazines and from thesuitable malonic acids monoalkyl or mono-benzyl esters, optionally2,2-disubstituted, the following N,N'-disubstituted piperazines areobtained:

N'-[(1-(1'-malonyl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[2,6-bis(diethylamino)pyrimidin-4-yl]piperazine,m.p. 168°-170° C.,

N'-[(1-(1'-malonyl)pyrrolidin-2-yl)methyloxycarbonyl ]-N-[2,6-bis(allylamino)pyrimidin -4 -yl]piperazine,

(-)-N'-[(1-(1'-malonyl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine,m.p. 169°-170° C., [α]_(D) =-38.1'(c=0.2 in EtOH),

N'-[(1-(1'-malonyl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[4,6-bis(allylamino)-1,3,5-triazin-2-yl]piperazine,m.p. 177°-181° C.,

N'-[(1-(1'-malonyl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[4,6-bis(diethylamino)-1,3,5-triazin-2-yl]piperazine,

N'-[(1-(1'-malonyl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[3,6-bis(diethylamino)pyridin-2-yl]piperazine,m.p. sodium salt 198°-199° C.,

N'-[(1-(1'-malonyl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[3,6-bis(pyrrolidin-1-yl)pyridin-2-yl]piperazine,m.p. sodium salt 203°-205° C.,

N'-[(1-(1'-malonyl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[3,6-bis(allylamino)pyridin-2-yl]piperazine,

N'-[(1-(1'-malonyl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[3,6-bis(N-ethyl-N-allylamino)pyridin-2-yl]piperazine,

N'-[(1-(1'-malonyl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[3-ethylaminopyridin-2-yl]piperazine,m.p. sodium salt 200°-201° C.,

N'-[(1-(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[2,6-bis(diethylamino)pyrimidin-4yl]piperazine,

N'-[(1-(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[2,6-bis(allylamino)pyrimidin-4yl]piperazine, m.p. 161°-162° C.,

N'-[(1-(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)-methyloxycarbonyl]-N-[4,6-bis(allylamino)-1,3,5-triazin-2-yl]piperazine,m.p. 167°-170° C.,

N'-[(1-(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)-methyloxycarbonyl]-N-[4,6-bis(diethylamino)-1,3,5-triazin-2-yl]piperazine,

N'-[(1-(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)-methyloxycarbonyl]-N-[4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl]piperazine,m.p. 172°-173° C.,

N'-[(1-(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[3,6-bis(diethylamino)pyridin-2-yl]piperazine,

N'-[(1-(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[3,6-bis(pyrrolidin-1-yl)pyridin-2-yl]piperazine,m.p. potassium salt 206°-209° C.,

N'-[(1-(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[3,6-bis(allylamino)pyridin-2yl]piperazine,

N'-[(1(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[3,6-bis(N-ethyl-N-allylamino)-pyridin-2-yl]piperazine, m.p. sodium salt210°-213° C.,

N'-[(1(2',2'-dimethyl-1'-malonyl)pyrrolidin-2-yl)methyloxycarbonyl]-N-[3-ethylaminopyridin-2-yl]piperazine, m.p.potassium salt 220°-225° C.

We claim:
 1. Compounds of general formula (I) ##STR12## the singleenantiomeric and diastereomeric forms thereof, the mixtures thereof andthe pharmaceutically acceptable salts thereof with pharmaceuticallyacceptable acids and bases, wherein:B is a --CO--, --CH₂ OCO--, --CH₂OCS--, --CH₂ NHCO--, --CH₂ NHCS-- group; D is a 5-6 membered heterocyclehaving 3-5 carbon atoms and 1-3 nitrogen atoms in the ring, theheterocycle being unsubstituted or substituted with 1 or 2 amino,mono-C₁ -C₆ alkylamino, mono-C₃ -C₇ -alkenyl- or mono-C₃ -C₇alkynylamino, di-C₁ -C₆ -alkylamino, (C₁ -C₆)alkyl (C₃ C₇)alkenylamino,piperidin-1-yl, morpholin-4-yl or pyrrolidin-1-yl groups; Ra and Rb areindependently hydrogen or C₁ -C₃ alkyl or, taken together with thecarbon atom to which they are linked, form a C₃ -C₆ -cycloalkyl group;and n is an integer from 1 to
 4. 2. Compounds according to claim 1,wherein as D is selected from [2,6-bis(diethylamino)-4-pyrimidinyl],[2,6-bis(allylamino)-4-pyrimidinyl], [2,6-bis(amino)-4-pyrimidinyl],[2,6-bis(pyrrolidin-1-yl)-4-pyrimidinyl],[4,6-bis(allylamino)-1,3,5-triazin-2-yl],[4,6-bis-(diethylamino)-1,3,5-triazin-2-yl],[4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl],[3,6-bis(diethylamino)-pyridin-2-yl],[3,6-bis(pyrrolidin-1-yl)pyridin-2-yl],[3,6-bis(allylamino)pyridin-2-yl],[3,6-bis(propargylamino)pyridin-2-yl],[3,6-bis(N-ethyl-N-allylamino)pyridin-2-yl], [3-ethylaminopyridin-2-yl].3. Compounds according to claim 1, wherein B is a --CO-- or --CH₂ OCO--group; D is heterocycle selected from[2,6-bis(pyrrolidin-1-yl)-4-pyrimidinyl],[4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl],[3,6-bis(diethylamino)pyridin-2-yl] and [3-ethylaminopyridin-2-yl]; Ra,which is the same as Rb, is hydrogen or methyl and n=1.
 4. A process forthe preparation of the compounds of the compounds claim 1, characterizedin that a compound of formula (II) ##STR13## wherein B and D are asdefined above, is reacted with a compound of formula (III) ##STR14##wherein Ra, Rb and n have the above described meanings; R is a leavinggroup which can easily be removed; E is chlorine, bromine, N-imidazolyl,OH, O-hydroxysuccinimidyl or, taken together with the carbonyl group, itforms a mixed anhydride with a carboxylic or sulfonic acid, to givecompounds of formula (Ia) ##STR15## and the R group is removed from thecompound of formula (Ia) to produce the compounds of formula (I).
 5. Aprocess according to claim 4, characterized in that the compounds offormula (Ia) ##STR16## wherein B, D, Ra, Rb and n are as defined aboveand R is C₁ -C₆ alkyl are hydrolyzed with mineral bases in suitableconcentrations and in a suitable solvent to produce the compounds offormula (I).
 6. A process according to claim 4, characterized in thatthe compounds of formula (Ia) ##STR17## wherein B, D, Ra, Rb and n areas defined above and R is allyl or benzyl, are catalyticallyhydrogenated to produce the compounds of formula (I).
 7. A processaccording to claim 6, characterized in that hydrogenation is carried outwith a catalyst selected from palladium on charcoal in variousconcentrations, nikel-Raney, palladium tetrakis(triphenylphosphine) in asuitable solvent or by means of hydrogen transfer procedures. 8.Pharmaceutical compositions containing a compound of claim 1 as theactive ingredient.
 9. A method of treating asthmatic or inflammatoryconditions of the respiratory tract in a patient in need of suchtreatment, comprising administering to the patient anasthmatic-condition-treating or inflammatory-condition-treatingeffective amount of a compound of claim
 1. 10. A method according toclaim 9, wherein the compound is administered in a dosage of 2-50 μg/kg.11. A method according to claim 9, wherein the compound is administeredat a daily dose of 1-50 mg.
 12. A method according to claim 11, whereinthe daily dose is divided into a plurality of individual doses.